Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies

• DOI: 10.3390/ph16010095
• Publication Date: 2023-01-09T12:28:10Z
• Authors: Raquel B. M. de A...; Deyse B. Barbosa; Mayra R. do Bomfim; Jéssika A. O. Amparo; Bruno S. Andrade; Silvia L. Costa; Joaquín M. Campos; Jorddy N. Cruz; Cleydson B. R. Sa...; Franco H. A. Leite; Mariana B. Botura
• Keywords: Butyrylcholinesterase; Cholinesterase; IC50; Viability assay

The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment Alzheimer's disease. This study aimed to evaluate in vitro effect ZINC390718, previously filtered using computational approaches, on both cholinesterases characterize, molecular dynamics (MD) simulation, possible binding mode this compound inside cholinesterase enzymes. cytotoxicity was also investigated primary astrocyte-enriched glial cell culture. ZINC390718 presented dual inhibitory activity against AChE at high micromolar range (IC50 = 543.8 µM) BuChE 241.1 concentration-dependent manner, with greater BuChE. MD simulation revealed that performed important hydrophobic H-bond interactions catalytic residue sites targets. residues promoted H-bonding target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, Tyr341, target, they Asp70, Tyr332, Tyr128, Ile442, Trp82, Glu197. cytotoxic Z390718, evaluated viability, showed molecule has low toxicity. silico results indicate can be used as chemotype optimization identification new inhibitors.